PROJECT SUMMARY/ABSTRACT The central nervous system is acknowledged as a major regulator of both energy and glucose homeostasis. Our data demonstrates that dietary protein restriction increases energy expenditure and improves glucose homeostasis, and that this effect is largely mediated by the metabolic hormone FGF21. Indeed, our data suggest that FGF21 is the only known endocrine hormone that specifically coordinates adaptive responses to protein restriction. Therefore, this project uses the model of dietary protein restriction to probe the physiological mechanisms through which FGF21 influences energy expenditure and glucose homeostasis, specifically testing whether FGF21 signaling within the CNS is required for the metabolic effects of protein restriction. This model will be tested by deleting the required FGF co-receptor beta-Klotho (Klb) from neurons, and determining if mice lacking CNS FGF21 signaling fail to exhibit increased energy expenditure or improved glucose homeostasis when placed on a low protein diet. Considering our current lack of certainty regarding the mechanisms through which FGF21 acts, this work will both define the contribution of the CNS to FGF21 signaling while also delineating the first known neuroendocrine model to explain the coordinated metabolic changes induced by dietary protein restriction.